Increased cardiovascular mortality and morbidity are observed in NAFLD.
ReviewNon-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications
Introduction
Non-alcoholic fatty liver disease (NAFLD) has become a major cause of chronic liver disease in Western societies and will become the main underlying cause for liver transplantation within 10 years [1]. Although awareness amongst physicians has increased and the importance is recognised, levels of screening and referral to hepatologists in suspected NAFLD is low in primary care and non-hepatology specialties [2], [3]. As a result, NAFLD is relatively underdiagnosed and long-term outcomes of hepatic and extrahepatic manifestations of NAFLD are compromised. Indeed, NAFLD is not only associated with increased liver-related morbidity and mortality, but also with increased mortality due to cardiovascular disease (CVD) and cancer [4], [5].
The role of NAFLD as an independent cardiovascular risk factor is still debated. Several studies demonstrated unequivocally an increased cardiovascular (CV) mortality in NAFLD [4], [6]. Nevertheless, some studies failed to confirm this association, including two large cohort studies with long-term follow-up [7], [8]. However, the data should be interpreted with caution because of several methodological issues, including retrospective diagnosis based on recorded ultrasound imaging or on biochemistry [7], which is known to poorly correlate with histological NAFLD features [9]. Even in the absence of a significant relation with CV mortality, CVD was still undoubtedly increased in NALFD patients compared to controls [8], supporting the many convincing data that NAFLD independently contributes to (sub)clinical CVD.
Distillation of NAFLD as a separate risk factor is impeded by overlap with other well-established risk factors for CVD, as they are also risk factors for NAFLD itself [5]. Assuming that NAFLD is a contributor to CVD implies the need for knowledge on the underlying pathophysiological mechanisms that explain how NAFLD independently impacts on CVD. An extensive overview of potential mechanisms is currently lacking.
In this review we summarise knowledge, originating from animal research as well as translational and clinical research, about the underlying pathophysiological mechanisms that might link NAFLD to CVD. We subsequently discuss the potential implications of these findings for clinical management of patients with NAFLD and future research goals.
Section snippets
General considerations
The specific contribution of NAFLD to increased CVD risk is, especially in clinical studies, difficult to dissect from the combination of risk factors that are shared by both NAFLD and CVD. The population of NAFLD patients is furthermore probably heterogeneous, in some of whom NAFLD is just part of and victim of the global metabolic derangement whilst in others, the liver is particularly involved in the pathophysiology of the Metabolic Syndrome (MetS) itself, and in the emergence of CVD and
Potential pathophysiological mechanisms
The mechanisms explaining development of CVD in NAFLD are not completely understood. NAFLD is part of a complex multisystem disease with multiple bidirectional relationships. Moreover, each individual patient might exhibit a unique combination of causal mechanisms. The next section summarises the different potential mechanisms by which NAFLD may contribute to CVD (Fig. 2; Table 1). These mechanisms are rather complex, incompletely known and often interrelated.
Current guidelines
In the current published recommendations, both on the clinical management of the patients with NAFLD and a fortiori on the design of therapeutic trials for NAFLD, the link with CVD disease is not a major issue [180], [181], [182]. In the clinical guidelines, the overt link of NAFLD with the MetS translates into instructions to screen NAFLD patients for associated CVRFs and to treat these according to their proper guidelines [15]. In the joined AASLD-AGA guidelines, these instructions are only
Conclusions
The liver and the cardiovascular system are inextricably linked to each other: the hepato-cardiovascular axis.
CVD remains the most important cause of death in patients with NAFLD. Clinical evidence for a hepato-cardiovascular axis, in which NAFLD is an independent risk factor for subclinical and clinical CVD is supported by evidence from fundamental and clinical research; unravelling the mechanisms by which NAFLD causally influences endothelial dysfunction and the development of atherosclerosis
Financial support
WK and SF received funding from the fund for scientific research (FWO) flanders (11j9513n, 1802154n). The funders had no role in the preparation of the manuscript.
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Authors’ contributions
All authors contributed to the draft of the text. Furthermore, the intellectual content was subject to critical review by SF and WK. DG created the figures.
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